Lower urinary tract symptoms (LUTS), including bladder voiding symptoms, are a common problem in aging men. Voiding symptoms occur in many cases due to bladder outlet obstruction (BOO). While the underlying causes of BOO are unclear and may be multi-factorial, BOO is often found in association with benign prostatic hyperplasia (BPH), another highly prevalent condition in aging men. While the etiology of BPH and BOO remain largely unclear, available data are consistent with the hypothesis that changing hormone levels in aging men and/or the reactivation of developmental growth-regulatory pathways are underlying causes of BPH and associated BOO. In support of the potential role of steroid hormones in BPH and BOO, our preliminary studies showed that male mice treated with testosterone + estradiol (T+E2) at doses that mimic the hormonal milieu in aging human males developed benign enlargement of the prostate that was associated with the appearance of proliferating foci along the urethra that resembled developmental prostatic buds, changes in the morphology of the prostatic peri- urethral region, and a high incidence of urinary retention indicative of BOO. Strikingly, the severity of hormone-induced urinary retention was more than 4-fold greater in 18-month-old mice compared to 2-month-old mice indicating that this model recapitulates the age-dependent susceptibility to BOO that is also seen in humans. The hormone-induced mouse model also exhibited gene expression changes in the prostate that have been reported to occur in human BPH associated with BOO, including the up-regulation of Secreted frizzled related protein 1 (Sfrp1). Using several approaches including the creation and study of Sfrp1 knockout and transgenic mice as well as in vitro experiments, our published and preliminary studies have implicated Sfrp1 signaling via the non-canonical WNT/JNK pathway as a pro-proliferative signal during prostatic development that can be co-opted to trigger abnormal proliferation in the adult prostate. These data suggest that Sfrp1 is likely to be a mediator of BPH pathology rather than merely a biomarker for BPH. We hypothesize that a sub-type of BPH associated with BOO is caused by the reactivation of developmental growth-regulatory pathways including SFRP1/JNK signaling. This hypothesis will be tested using a multi-disciplinary approach that will include an evaluation of mouse models and a collaboration with a surgical pathologist, Wei Huang M.D., who will assist us in evaluating developmental growth factor pathways and JNK signaling in human patient samples. PUBLIC HEALTH RELEVANCE: Benign prostatic hyperplasia (BPH) and bladder outlet obstruction are common problems in aging men that often occur together and require medical intervention ranging from drug therapy to surgery. The limitations of current therapies create a need for additional treatment options for men suffering from BPH and bladder outlet obstruction. This project addresses the need for additional treatment options by conducting mechanistic studies that will identify new molecular pathways that drive the development of BPH and bladder outlet obstruction. It is anticipated that these molecular pathways will serve as future therapeutic targets in the clinical management of BPH and bladder outlet obstruction.